Problems in early drug development: PARP inhibitors, an example of a problematic class Ruth Plummer TAT2014
Ruth Plummer, MD, PhD I have been involved in the clinical development of rucaparib (AG014699, CO338) for 11 years, receiving clinical trial support and research funding from Pfizer GRD and Clovis Oncology I am listed on a patent of use of AG014699 I also have received clinical trials funding for studies with Olaparib, veliparib, iniparib, CEP-9722, BM673, E7449 I have advised on the development of olaparib, niraparib, rucaparib
Ruth Plummer, MD, PhD Receipt of Intellectual Property Rights / Patent Holder: Patent of use of rucaparib (Clovis) Consulting Fees (e.g., advisory boards): Roche, BMS, GSK, Clovis, Vertex I intend to reference unlabeled/unapproved uses of drugs or products in my presentation: olaparib, rucaparib, veliparib, niriparib
The PARP superfamily PARP-1 is founder and best characterised PARP-2 Identified by sequence homology to PARP-1 catalytic domain. Only PARP-1 and PARP-2 known to be activated by and repair DNA breaks PARP-1 yellow PARP-2 grey NAD blue
Role of PARP-1 in BER/SSBR 18 members of PARP super-family identified to date PARP-1 PARP-1 abundant nuclear enzyme activated by and binds with high affinity to DNA single and double strand breaks via zinc fingers N A - DNA binding domain ZF D - Automodification domain ZF NLS C BRCT E F - Catalytic domain C PARP-1 essential for the repair of damaged bases and single strand breaks via the Base Excision repair pathway B - Nuclear localisation signal XRCC1
The problems in clinical development Timelines Pre-clinical science ~ 15-20 years Clinical development ~ >10 years Strategy Dual strategy in the clinic Single agent Combination therapy Biomarkers
Development of the first in class PARPi targeting the NAD + binding site common to all PARPi apart from iniparib NAD + N N NH 2 N N OH OH O * Attachment point Linear chain Branched Chain O O O P P - O OH O O ADP ribose OH - O OH + N * O N H H Nicotinamide Bond undergoing Cleavage Based on the catalytic mechanism: analogues of the by-product, nicotinamide NH 2 O NH 2 3-aminobenzamide (3AB) Ki = 10 M O NH H N CH 3 N N 1980 OH HN 1996 N 2001 HN 2003 NU1025 Ki = 48 nm 1990 Newcastle Chemists CRUK funding O NU1085 Ki = 6 nm NH OH O NH AG14361 Ki < 5 nm N Wat-52 Glu-988 2.7 2.8 Tyr-889 F Agouron Chemists Ser-904 2.9 O 2.8 AG14361 3.2 NH 2.9 Gln-763 AG 14447 Ki < 5 nm Gly-863 Asp-766 N
PARP Inhibitors in Clinical Trials Agent Company Single/Combination therapy Route of administration Disease area Current Clinical status AG014699 (PF0367338, CO338) (rucaparib) 2003 Clovis/Pfizer Combination ++/single I.v. And oral Cancer Phase III KU59436 (AZD2281) (olaparib) 2005 AstraZeneca/ KuDOS Single/ Combination ++ Oral Cancer Phase III ABT-888 (veliparib) 2006 Abbott Laboratories Single/ Combination ++ Oral Cancer Phase III BSI-201 (SAR 240550) Iniparib 2006 SanofiAventis/ BiPar Combination with gem carbo, tmz I.v. Cancer Phase III completed INO-1001 2005/6 Inotek/ Genentech Combination with temozolomide, single I.v. Re-perfusion injury Reformulation? MK4827 (Niraparib) 2008 Merck/Tesaro Single Oral Cancer Phase III (E7016, 2010) (E7449, 2012) GPI 21016 Eisai/ MGI Pharma Combination with temozolomide Oral Cancer Phase I CEP-9722 2009 Cephalon Combination with temozolomide Oral Cancer Phase I LT673 (BM673) 2011 Biomarin/LEAD Therapeutics Combination/single Oral Cancer Phase III JPI-289 2014 Jeil Pharmaceutical Co Single agent i.v Inflammation Healthy volunteer dose finding
More recent drug development timelines Gandhi and Janne CCR 2012 Vemurafenib (PLX4032) entered phase I in 2008,completed phase III 2010 Licensed 2011
Mis-classification of iniparib has not helped O Shaughnessy et al SABCS 2009 poster 3122 Iniparib is not a bone fide PARP inhibitor Non-selective modification of cysteine-containing proteins (Liu et al CCR 2012 18 510-523 No selectivity for HRD cells, does not sensitise to top 1 inhibitors, and no PARP inhibition in cell based assay (Patel et al CCR epub Jan 2012) But there are patient groups who benefit
Current status 102 studies listed on www.clinicaltrials.gov 31 actively recruiting patients 5 agents in phase III studies ARIEL3 - rucaparib as switch maintenance in HGSO SOLO 1 and 2 Olaparib after platinum response in BRCA ovarian cancer and as maintenance (2 studies) BRAVO niraparib v physicians choice in BRCA breast cancer BMN673 v physicians choice in BRCA breast cancer Brightness veliparib + carbo v carbo added to standard neo-adjuvant chemotherapy in TNBC
Dual Strategy for clinical development
PARP inhibitors potentiate radiotherapy and DNA damaging chemotherapy Temozolomide Irinotecan Median RTV 12 11 10 9 8 7 6 5 4 3 2 1 Median RTV Control 699 10 TM 68 TM 68 + 699 0.1 TM 68 + 699 1.0 TM 68 + 699 10 0 0 10 20 30 40 50 60 70 Day Radiation
Single agent activity - Synthetic Lethality Spontaneous DNA damage within cell: 20,000 SSB 10,000 depurinations Why am I here? BRCA heterozygote cell BRCA mutation -/-cell BRCA -/- cancer cells BRCA +/- normal cells Adapted from Bryant et al. Nature 2005; 434:913-917
Single agent activity and dose response in BRCA patients 400 mg BD 100 mg BD Tutt et al The Lancet 2010 376(9737):235-44 EMA has accepted a Marketing Authorisation in BRCA ovarian cancer based on sub-group analysis of Study 19 data
Fools rush in where angels fear to tread lessons from the past! Alexander Pope An Essay on Criticism 1709 The Bookful Blockhead, ignorantly read, With Loads of Learned Lumber in his Head, With his own Tongue still edifies his Ears, And always List'ning to Himself appears.
Blocking direct repair to overcome chemotherapy resistance Carmustine Recommended dose for combination 40 mg/m 2 carmustine + 120 mg/m 2 O 6 -benzylguanine Carmustine dose has to be reduced to 20-25% of single agent dose O 6 benzylguanine Schilsky et al, Clin Cancer Res 6:3025, 2000
PARPi chemo-potentiation studies enhanced myelosuppression is dose limiting Olaparib gemcitabine/cisplatin Paclitaxel DTIC Veliparib Topotecan Cyclophosphamide temozolomide Rucaparib temozolomide cis/pemetrexed carboplatin
Consequences of dual strategy (and too many drugs?) Dose Single agent dose much greater than can be safely given in combination Olaparib 300 mg BD continuously v 100mg bd intermittently Rucaparib 600 mg bd continuously v 360 mg OD intermittently in combination No focus on PD biomarkers and how much enzyme inhibition is needed in each setting
Biomarkers
BRCA 1 and BRCA 2 germ line mutations Predominant registration strategy in metastatic setting Can we safely use in adjuvant setting to avoid surgery? hair follicle γh2ax biomarkers (Fong et al NEJM 2009) Myelodysplasia and pneumonnitis There is activity in non-brca related tumours Gelmon et al Lancet Oncol 2011 12 852-861 Ovarian cancer BRCA-related and HGSO non- BRCA (confirmed in AZ Study 19) Continued debate in TNBC without a BRCAmutation
Biomarker development for HRD Primary cell culture for RAD51 foci formation after DNA damage Gene expression profiling to identify a genetic signature of HRD Multiple groups and companies investigating Markers of DNA damage and response in tumour biopsies after treatment Nick Turners work in neoadjuvant breast cancer demonstrating low RAD51 score after DNA damage as predictor of HRD and sensitivity to chemotherapy CTCs in patients after treatment Shivaani Kummar and colleagues at NCI demonstrated increased γh2ax foci after veliparib and topotecan
Functional biomarker assay for HRD γh2ax/rad 51 assay based on the principle of synthetic lethality Co-localization of γh2ax and RAD51 foci in HR competent cultures
We need biomarker assay development Ability to form RAD51 foci i.e repair DSB in primary ascites cultures Cytotoxicity to 10 µm AG014699 Synthetic lethality Mukhopadhyay et al, CCR 2010
Are we going to sort out the problem child? PARPi likely to be used in combination even to exploit HRD Single agent activity in HRD but not curative even in BRCAdefective background Scheduling to avoid the chemotherapy in HRD? Treatment breaks for normal tissue recovery with DNA damaging agents Biomarkers treat the right patients BRCA1, BRCA2, PTEN loss Functional HRD assay in sporadic cancers Gene signatures and patient enrichment Liquid assays CTC and cfdna
Acknowledgements NICR team Patients Clinical research team Hilary Calvert Nicola Curtin Herbie Newell Roger Griffin Chris Jones Yvette Drew Alan Boddy Barbara Durkacz Bernard Golding
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